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spk02: Welcome to the INSMED four-quarter and full-year 2021 financial results. My name is Juan, and I will be coordinating your call today. If you would like to ask a question during the presentation, you may do so by pressing star 1 on your telephone keypad. I will now hand over to your host, Eleanor Bereser, Investor Relations at INSMED, to begin with. Please, Eleanor, go ahead.
spk08: Thank you, Juan. Good morning and welcome to today's conference call to discuss our full year financial results for 2021 and to provide a business and pipeline update. Before we start, let me remind you that today's call will include forward-looking statements based on current expectations. Such statements represent our judgment as of today and may involve risks and uncertainties that may cause actual results to differ materially from the results discussed in the forward-looking statements. Please refer to our filings with the Securities and Exchange Commission, which are available through the SEC's website at www.sec.gov or from our website for information concerning the risk factors that could affect the company. The information on today's call is not intended for promotional purposes and not sufficient for prescribing decisions. Joining me on today's call are members of the Internet Executive Management Team, including Will Lewis, Chair and Chief Executive Officer, Dr. Martina Flammer, Chief Medical Officer, Roger Asset, Chief Operating Officer, and Sarah Bonsdien, Chief Financial Officer. Let me now turn the call over to Will Lewis for prepared remarks. Upon completion of those remarks, we will open the call up for your questions.
spk11: Thank you, Eleanor, and good morning, everyone. Today is a very exciting day for us at INSMED. We are going to share with you a robust set of updates that will clarify how we are thinking about our program catalysts, commercial franchise, and capital allocation over the next several years to support our mission of transforming the lives of patients with serious and rare diseases. At Intamed, we are building what we believe is one of the few companies in our industry capable of producing potentially multi-billion dollars of revenue by the end of this decade. During the course of today's call, we are excited to review the path we will be following as we pursue this ambitious goal. Our strategy is centered on developing medicines that have a significant positive impact on patients' lives. Today, Insomed has seven ongoing mid- and late-stage clinical trials, commercial operations in three territories around the globe, and a research engine working behind the scenes to identify the most promising early-stage candidates by harnessing innovative technologies. We have segmented all of this work into four pillars. The first of these pillars is the Ericase franchise, our marketed product for the treatment of refractory MAC lung disease, where we benefit from a commercial footprint in the US, Europe, and Japan. As these launches mature, we intend to grow revenue globally by at least 30% this year compared to 2021. In parallel, our frontline clinical trial program is advancing to support full FDA and select international approvals of Ericase in newly diagnosed NTM patients. This frontline indication represents a multi-fold increase in the addressable opportunity compared to the refractory setting alone. The ARISE study, which is the first of the two studies needed on our path to approval, is currently 50% enrolled, and we anticipate enrollment to be complete this year with top-line data in the first half of next year. We also anticipate the second study, ENCOR, will be fully enrolled next year. For our second pillar, Brenzocatib, our DPP-1 inhibitor, the Aspen trial exploring the potential of treatment of bronchiectasis is now 50% enrolled, ahead of internal projections, and we anticipate it will be fully enrolled by approximately this time next year. There is real enthusiasm for this trial around the world as this rapid rate of enrollment testifies. In addition to Aspen, the Phase II PK-PD study in cystic fibrosis patients is underway, and we anticipate top-line data by the end of this year or early 2023. In line with our strategy to build a portfolio around neutrophil-mediated diseases using our DPP-1 inhibitor, we are excited to report that we have identified the next two potential indications for renzocatin, along with Phase II clinical trial designs for their exploration. You will hear more about these later on today's call. Our third pillar, TPIP, is a specialized proprosenil prodrug formulation with three parallel phase two programs underway, with an initial focus on potential treatments for PAH and PHILD. We will also review those trial designs later on the call. Finally, translational medicine is our fourth pillar. Led by several world-class teams, our research engine is working with exciting new technologies to identify the next round of incidence early stage pipeline candidates in the serious and rare disease space. Within this framework, we intend to generate, on average, one new IND per year. We look forward to hosting a detailed research day in the second half of this year to update you on our progress. Set against the backdrop of one of the more challenging healthcare markets in recent years, I believe Insumet is poised to weather the storm of these turbulent times. Our goals are ambitious, but we have been deliberate in our pursuit, and we have a track record of achieving what we set out to do. The next stage of our growth will depend on advancing more treatments and strategically complementary indications, and from there, building additional therapeutic areas from our fourth pillar to follow the first three pillars. Let's take a moment to consider what we have accomplished. Our global commercial franchise and infrastructure is already built. We benefit from revenue generation from our marketed product. We have two strategically overlapping pivotal stage programs with Brent Sokative and Eric Case Frontline. We have a robust pipeline, a focused research effort to generate impactful medicines in new therapeutic areas, and a strong cash position. InnsMed is on a path to realize this bright future for the benefit of our patients and our shareholders. All of this is overseen by a world-class leadership team with an impressive track record of executing commercial, clinical, and regulatory pathways, who will now review where we stand in greater detail. Let me start that process by turning the call over to Sarah to walk through our financial results.
spk08: Thank you, Will. Good morning, everyone. A key priority for 2021 was maintaining financial strength, and we made important strides on this front. We bolstered our balance sheet and continued to benefit from the error case revenue stream while exercising fiscal discipline. As a result, we are in a favorable position with balance sheet strength as we evaluate the many opportunities inherent in our existing portfolio. Earlier today, We issued our detailed fourth quarter and full year financial results in a press release. All of those results are aligned with our internal expectations. Let me highlight a few of our full year results for you now. As reported this morning, we ended the year with $766.8 million in cash and cash equivalents and marketable securities. We believe this cash position will support our ongoing business into 2024. There are three main variables that impact our cash position. First, revenue from our marketed product. Second, how fully and broadly, as well as when we choose to pursue the programs in our development pipeline. And third, how we resource launch readiness for several of these substantial programs, including inventory build. We will carefully consider these elements as we craft our plans forward. Now, turning to the financials. Total net revenue for Aircase was $188.5 million for the full year 2021. As we look to each of our commercial regions, net revenue for 2021 was $159.5 million in the U.S., $16 million in Japan, and $12.9 million in Europe and rest of the world. Notably, Our U.S. revenue number for the full year 2021 demonstrates steady performance of the Aircase franchise over the prior year, despite the rise and fall in infection and hospitalization rates in the shifting COVID landscape. We are encouraged by the overall improvement in the way in which people have adapted to the new realities presented by COVID around the globe. Consequently, these elements give us confidence that we will return to growth this year in all of the regions we are pursuing. On a global basis, we anticipate seeing meaningful growth in error case revenue this year and are prepared to forecast at least 30% revenue growth year over year for 2022. Our growth to net in the U.S. for the full year of 2021 were approximately 13.2%. Looking ahead at 2022, we anticipate growth to net in the U.S. to be in the mid-teens, consistent with our estimates from prior years. Recall that in the U.S., the first quarter is typically the toughest due to the deductible and copay recess for our Medicare patients that occur at the beginning of the year, resulting in the donut hole effect. As a result, we expect to see a similar trend to what we have historically experienced from fourth quarter to first quarter revenue levels. Cost of product revenues for the full year 2021 was $44.2 million, or 23% of revenues. This is consistent on a percentage basis with the cost of product revenues in the full year of 2020. Turning to our GAAP operating expenses. For the full year of 2021, research and development expenses were $272.7 million and SD&A expenses were $234.3 million. In closing, Intimate has entered 2022 in a very strong capital position as we support the four pillars of our business. We intend to be responsible stewards of cash with the foresight to invest now to unlock the potential for candidates that may represent real improvements in healthcare for patients. I'll now turn the call over to Martina for an update on our clinical development pipeline. Martina? Thank you, Sarah, and good morning, everyone. 2021 marks another transformational year for Intimate with respect to our clinical trial work. Today, I'm excited to be able to share important updates around several of our programs in development. Let's begin with brenzocathin, our TPP-1 inhibitor, targeting neutrophil-mediated diseases. I'm pleased to report that our Phase III asthma study for the potential treatment of bronchiectasis is now 50% enrolled, and we anticipate enrollment to be complete at approximately this time next year. Let me remind you that this trial is expected to enroll more than 1,600 patients at more than 400 clinical sites around the world. If there is one takeaway I can leave you with, it is this. For Aspen to be halfway enrolled in just one year is an extraordinary achievement, and we believe this milestone demonstrates significant enthusiasm for the potential of translocathets for bronchiectasis patients. We are grateful to our investigators and to patients who have dedicated their time to this program at a very challenging time in respiratory medicine. I'm also pleased to share that the first meeting of the Data and Safety Monitoring Board, or DSMB, took place at the end of last year, where it was recommended that the asking trials continue as planned. Recall that bronchiectasis is a globally prevalent disease with no approved treatment and with over a million patients diagnosed worldwide. This represents an enormous opportunity for our compound. Furthermore, we believe COPD and asthma patients who may have undiagnosed bronchiectasis present additional market opportunities given the comorbidity of these indications. Let's now turn to the next area of bransocaptive development in cystic fibrosis. We are on track to release results this year, or early 2023, from the Phase II PKPD study, which will be instructive as to the appropriate dosing strength for CF patients. The trial is a single-blind assessment of once-daily bransocaptive at 10, 25, and 40 milligrams versus placebo in 36 patients with CF. Treatment duration is 28 days, and we will evaluate PK and safety data, as well as reduction of NSB levels in sputum and blood, along with other exploratory spirometry measurements, such as FEV1. Following a review of safety and PK data, there is optionality to go to a 65 mg dose, which may be warranted given CF patients often have different metabolic profiles versus non-CF patients. All toxicology work to support higher dose levels has been completed. The tremendous success of our Phase II rule study highlighted the efficacy of DPP-1 inhibition in treating bronchiectatic patients and suggests its potential role in treating CF patients. In addition, what excites us is the pathway of DPP-1 inhibition for the treatment of many neutrophil-mediated diseases. And we have been doing significant work to explore how our compound may benefit patients in other disease areas. I'm excited to share with you today that we are moving pranzocapit into two new potential indications, chronic rhinosinusitis without natal polyps, or CRS, and hydradenitis superativa, or HS. These indications are an exciting new chapter in branchocathet development, echoed by the enthusiasm from the deep bench of experts within INCMED who have experience in these disease states. We see clear scientific rationale supporting the potential role of branchocathet in pursuing these indications. As we are targeting the neutrophilic activity in the inflammatory pathway of disease, We believe that DPP-1 inhibition leading to a reduction of NSP levels may be able to interrupt the inflammatory components of these diseases. First, it's important to distinguish CRS without nasal polyps, which we are targeting, from CRS with nasal polyps. Both can be severe diseases, but with CRS without polyps, we generally see more neutral recruitment in the inflammatory process. aligning with the mechanism of action demonstrated by Brenzer tactics. There are currently no approved therapies for patients with CRS without nasal polyps, which is the most common type of rhinosinusitis. CRS without nasal polyps is characterized by chronic inflammation and fibrosis of the mucous membranes inside the sinuses. The most common symptoms include a nasal obstruction, decreased sense of smell, and facial pain. Patients with CRS also report lower quality of life measures, impacting bodily pain, general health, physical and social functioning, and the diseases associated with increased rates of depression. Currently, the only available treatment options for patients with CRS without polyps are corticosteroids, antibiotics, or endoscopic procedures. These endoscopic surgeries may have to be repeated. We are targeting patients at the severe end of the disease spectrum for whom surgery does not work. All of these signals that we need an urgent need for a safe oral therapy for these patients. Let's now turn to HS. HS is a chronic inflammatory skin disorder characterized by painful, inflamed, and swollen lesions affecting hair follicles, often in the armpits, groin, and skin folds. The clinical course is variable, ranging from relatively mild disease characterized by the recurrent appearance of inflamed lesions and nodules to severe cases with steep abscesses, strained fistulas, and severe scars. Patient-reported quality of life measures indicate a high psychosocial impact from the disease with increased rates of anxiety and depression. We are targeting the moderate to severe end of the disease spectrum, there is only one approved therapy for HS, which does not work for all patients. And given the complexity of the disease, patients can require multiple treatments and sometimes surgery to maintain control of the disease. We have seen enthusiasm among healthcare professionals for investigational therapies to help identify new effective treatment options for both HS and CRS. Let me take a moment to walk through the study designs. Our current plan is to move CRS into the clinic in a Phase II study over a 24-week treatment period, exploring pranzo-cathib at 10 and 40 milligrams versus placebo, followed by four weeks off therapy, with the primary endpoint of change in an established measure of total symptom score. Let's now turn to the trial design in HS. We anticipate that our Phase II trial in HS will span a 16-week treatment period, exploring 10 and 40 mg of francer catheters versus placebo, followed by a 36-week open-label extension period. The primary endpoint will be percentage of subjects achieving hydroadrenitis superativa clinical response at week 16. All of this aligns with our broader strategy of building a portfolio around the DPV-1 inhibition pathway to target neutrophil-mediated diseases. We anticipate advancing one of these new indications into the clinic this year, and we will have more to say about our overall progress with brentopaceptic in all indications in the next few quarters. Let's now turn to the ERICase Frontline Program. I am excited to report that the ARISE study is now 50% enrolled, and we anticipate reaching enrollment completion this year with top-line data from ARISE in the first half of 2023. We also anticipate ENCORE to be fully enrolled in 2023. As a reminder, data from ARISE will inform and allow us to finalize the PRO utilized in the ENCORE trial. These timelines are consistent with what we have seen in our previous NTM trials, reaffirming that enrollment of NTM trials typically proceeds at a slow pace. As was the case in our previous trials, positive student cultures are not always present at the time of patient screening, and it is not surprising to see screen failure rates surpass 40%. Recall that ARRIVE is preferentially enrolled over ENCORE with a randomization of 2 to 1. And once ARRIVE is fully enrolled, we anticipate enrollment in the ENCORE study to accelerate. As additional study sites come online, we also anticipate this will help drive enrollment momentum in ENCORE. In addition, Oncor is a more attractive study from a patient recruitment perspective because it provides an uninterrupted treatment cycle, allowing patients to stay on therapy for a full 12 months versus six months for a rise. This is a relevant factor for patients and physicians as they evaluate their participation in these clinical trials. We look forward to maintaining our enrollment momentum in both of these studies and will update you on our progress. I'll now turn to TPIP. TPIP is our troprostenol prodrug in Phase II development for both PAH and PHILD. This is an exciting opportunity, as we believe that our compound could envelope the full potential of the prostanoid pathway to benefit patients with certain rare pulmonary disorders. Let me take a moment to walk you through our Phase II trial design. The first study to discuss is the randomized double-blind placebo-controlled phase 2B study that will assess the efficacy, safety, and PK of TPIP in patients with PAH over a 16-week treatment period. Target enrollment in this study is approximately 100 patients. Patients will be dosed once daily, and each patient will be up-sitrated to his or her individual maximum tolerated dose. The primary measure is the change from baseline in pulmonary vascular resistance, or PVR, at week 16. And the key secondary measure will evaluate the impact of TPIP on six-minute walk distance at various time points. As planned, site initiation for the Phase IIb trial in PAH patients began late last year. We will update you on enrollment progress in the coming quarters. The second study to discuss is the randomized double-blind placebo-controlled phase 2 trial in PHILD, which will assess the safety and tolerability of TPIP over 16 weeks. Target enrollment is 32 patients. As with the study in PAH, patients will be dosed once daily, and each patient will be up-titrated to his or her maximum tolerated dose. Other key endpoints will include TPIP's PK profile, as well as various exploratory efficacy measures, including effects on six-minute walk distance. We think TPIP may be well-positioned for this indication by the way of inhaled route of administration, which delivers basal dilation to the ventilated areas of the lung. Systemically administered therapies, on the other hand, can lead to vasodilation in the areas of the lung that, due to fibrosis, are not ventilated, leading to a ventilation-perfusion mismatch. A TPIP route of delivery is intended to mitigate this problem with a potentially more favorable side effect profile, as well as longer lung residency time versus inhaled tyvesium. site initiation for the Phase II trial in PHILD patients is currently underway, and we look forward to keeping you apprised of our progress. Finally, the ongoing Phase II-A 24-hour right heart catheterization study evaluating PVR and PAH patients continues to look for volunteers, and we're hopeful that with Omicron receding, we will be successful in identifying volunteers and advancing enrollment. While this study is not great limiting to the other Phase II trials we have discussed, we are excited by the potential the results could suggest for our TPIP program and look forward to providing results from patients in this study as we collect data over the course of this year. I'd like to close by recognizing the significant and growing excitement behind our fourth pillar, translational medicine. This pillar is led by multiple teams and contains several exciting technology programs running in parallel, some of which are complementary to one another and others that are standalone therapies targeting different and unrelated conditions. We envision that some programs within these four pillars may act as platform capabilities, for example, the potential de-immunization of capsids and gene therapies. We anticipate that translational medicine will serve as the IND engine for INTIMID's future, thereby addressing the question of what may follow the anticipated success of our first three pillars. We hope to make significant progress from this effort in 2022, culminating in the filing of an IND in a new non-pulmonary indication by the end of the year. In parallel to this program, there are several other components of our fourth pillar, and we envision a detailed research date in the second half of this year, at which time we anticipate sharing preclinical data. While this represents an important pillar for our future, I continue to work closely with Sarah to ensure capital allocation to these areas remains measured and is deployed only with successful data along the way. In summary, INSMIT realized several major clinical achievements over the past year. 2022 is poised to be a critical year of execution across our clinical operations, and we look forward to delivering on the catalysts outlined today. With that, let me turn the call over to Roger to discuss some key operational updates.
spk11: Roger? Thank you, Martina, and good morning, everyone. From an operational standpoint, there are two main areas I want to focus on today. I'll start with the commercial operations surrounding our first pillar, Arrakase. From there, I'll turn to the expansion of our second pillar, Brenzocatib, and the additional clinical indications we have decided to target. For our Arrakase franchise, intimate commercial operations continue to perform extremely well over the course of 2021. Last year ushered in a new era for Arrakase, which is now launched in the US, Europe, and Japan. I'd like to take a moment to walk you through our recent progress in each of these regions. Let's begin with the U.S. The Our Case franchise has remained resilient throughout the ongoing pandemic, underscored by a solid fourth quarter performance, despite the arrival of the Omicron surges that rapidly swept the country beginning late last year. We continue to see regional variability across the U.S., with some areas more impacted by COVID than others. In particular, we have noted the impact of Omicron on the availability of workers in the medical setting, and we are all keenly aware of the pressure on healthcare professionals, particularly pulmonologists, infectious disease doctors, and respiratory therapists. However, despite these challenges, we believe we have the resources to achieve growth, as our therapeutic specialists continue to have positive interactions with physicians treating refractory NTM patients. Although COVID has impacted physicians' ability to see NTM patients, We also believe that the pandemic has brought to light a larger focus on pulmonary disease, and potentially a higher index of suspicion for refractory NDM. These factors, combined with our ability to adapt to the new circumstances of COVID, create potential for growth in the US and our international markets. Let's drill down into our ex-US commercial efforts. Beginning with Japan, where we are extremely pleased with the launch progress thus far, As a reminder, the launch of Japan began in July of last year. We believe that the opportunity in this market is significant and that in terms of revenue, Japan will be the second largest market for Aragaze after the U.S. Recall that for the first year of market availability in Japan, all drugs are restricted to a two-week dispensing limit. Practically, this requires the patient to return to their physician's office every two weeks to receive their prescription. This two-week restriction also impacts affordability for patients. Monthly patient co-pays are capped in Japan. So under the current restriction, a patient would receive a maximum of one month supply for their co-payment. Once this restriction is lifted in June, patients will be able to receive up to three months of Aricase for the same co-payment. In addition, the Japanese Society for Tuberculosis and Non-Tuberculosis Microbacterium published guidelines on the appropriate use of Aricase. recommending usage for patients who do not achieve culture conversion with a multi-drug regimen over six months. The guidelines also offer advice on managing adverse events. We see this as a positive development that may help physicians better understand the key considerations as they think about prescribing Aracase to their patients and managing the side effect profile. We are extremely excited about the opportunity in Japan and look forward to updating you on our progress. I'll now turn to Yerf. We anticipate the addressable market is smaller than those in the US and Japan. However, we have made excellent progress with physicians, and as reimbursement occurs in additional countries, we anticipate Europe will be a meaningful revenue contributor to the overall franchise. As we work to drive growth in this market, we continue to believe that the literature estimation of 1,400 diagnosed refractory MAG patients in Europe may be understated. Our case is currently available under a free pricing program in Germany, and the price is renegotiated after the first year on the market. We await a final pricing decision in Germany in the first half of this year. With the products also available and reimbursed in the Netherlands, Wales, and Scotland, we now turn our attention to England, France, and Italy as we await reimbursement decisions from those territories throughout this year. We have confidence in the future growth from each of our three regions where our case is available. As we continue to learn about and adapt to the realities of COVID, we believe we have the resources for our commercial operations to succeed in this challenging environment. I'd like to now turn to our second pillar, Renzocative, and the market opportunity in our newly announced indications, CRS and HS. CRS without nasal polyps represents a significant opportunity. There are approximately 33 million patients diagnosed with CRS in the U.S. Of those patients, approximately 26 million patients have CRS without nasal polyps. We are targeting the severe end of the disease spectrum, which represents a smaller though still substantial portion of the overall CRS without nasal polyps market. We believe a good proxy for severe disease are those patients who require surgical intervention. Each year in the U.S., approximately 155,000 patients undergo surgery for CRS without nasal palms. Of those, approximately 15% or 23,000 patients require revision or repeat surgery. We consider those patients undergoing repeat surgical intervention to be most severe. To be clear, these are annual incidence numbers and pending supportive clinical data, we expect these patients to take Brenzocatib chronically. As Martina mentioned, there are currently no approved treatments for this indication. If we are able to demonstrate clinically meaningful impact on this disease, we believe physicians may be inclined to try a well-tolerated effective therapy prior to recommending either initial or repeat surgery. we believe patients may also prefer a well-tolerated effective oral medication to surgical intervention. With HS, we estimate there are approximately 300,000 patients in the U.S. Approximately one-third of these patients, or about 100,000, have moderate to severe disease. We will be targeting the more severe patient group with brezocatin. Pumira is currently the only approved treatment for HHS patients, and we believe that Brenzocatib, a well-tolerated oral therapy with an attractive safety profile, will be a welcome addition to the treatment armamentary. We anticipate Brenzocatib will launch in bronchiectasis first. We believe this indication may support attractive pricing if we are able to show clinically meaningful impact on this disease. As we selected additional diseases to target, we wanted to ensure that the pricing was sustainable assuming we are also able to show clinically meaningful results. We believe the presence of improved biologics in both severe CRS with nasal polyps and HS validates the potential of these disease states to support strong pricing as well. When we take a step back and look at the overall picture of our BRENZOcative targeted indications, brachiectasis, cystic fibrosis, CRS, and HS, we see a pathway to what we believe is a very sizable market opportunity. In summary, the operational outlook at Intamed is strong. I'm proud of the team that has helped us execute on our milestones during a productive 2021. I look forward to what I believe will be another transformational year for the company. Now I'll turn the call back to Will. Thank you, Roger. I'd like to close out my remarks. by emphasizing Intamed's position of strength. Backed by a seasoned leadership team, a reliable and growing commercial franchise, a diverse pipeline of early to late stage assets, and a solid cash position, we have the elements we need to advance this company to the next level of growth. I believe Intamed can reach our goal of becoming one of the next great biotechnology companies. We will work to execute against the objectives we have laid out for you today for the benefit of our patients and our shareholders. I'd like to acknowledge the hard work from the entire INSEMED team, and I would like to extend my gratitude to the patients and caregivers who participate in our clinical studies. And with that, I'd like to open the call to questions. Operator, can we take the first question, please?
spk02: Of course. If you would like to ask a question, please press the star followed by one on your telephone keypad now. If you change your mind, please press the star followed by number two. Please limit yourself to questions per person so we have a chance to get around everyone. If you have any follow-up questions, you can join the queue again. When preparing to ask a question, please ensure your phone is unmuted locally. And the first question comes from Jessica Fai from JP Morgan. Please, Jessica, your line is now open.
spk01: Hey, guys. Good morning. Thanks for all the updates and for taking my question. For the 22 revenue guidance pointing to sales of at least $245 million for error case this year, I know you talked about growth in all regions, but can you help us think about the contribution from each geography that underpins that floor and maybe talk about the extent to which this might be conservative or how much conservatism you kind of reflect in that number? Thank you.
spk11: Yeah, sure. Appreciate that question. Look, I think we've all experienced the uncertainties that surround the pandemic's ebb and flow. What we tried to do with this forecast was to put out there a number that we feel very good about in terms of its defensibility, despite whatever may happen in the pandemic market. So I think there are Certainly the first quarter, as you know, is always the most challenging for the rare disease products, but we see a positive year across the board. I don't know, Sarah, if you want to add anything to that.
spk08: Yeah, no, thanks, Jess, for the question. Maybe just a couple other things to add. We're obviously very encouraged and excited to be able to share at least a 30% growth. That's obviously a meaningful growth year-over-year from 2021 to 2022. As Will mentioned, Q1 is the most challenging quarter in the U.S. due to the donut hole reset and all those good things that we see across high-price rare disease products. As the year progresses, Japan, we expect to be a meaningful contributor. As Roger mentioned, the second largest contributor in our three regions with that June time point as the list of the two-week prescription, which, you know, really helps patients from a copay perspective. So hopefully that gives you a little more color.
spk01: Great. Thanks. And if I could have a second question on CPIP. For that Phase IIb in PAH, what background therapies are allowed and what do you expect the mix of single and dual-agent background meds to be? And I know you're expecting better sort of coverage with PPIP relative to Tyveso, but do you expect the PBR data in the Phase IIb to compare well to Tyveso?
spk11: So I'll ask Martina maybe to take that.
spk08: Yeah, so, you know, we expect that what we've seen from TPIP in the healthy volunteer study is that we don't go up to such a high CMEX. We have a larger and a prolonged exposure on the AOC perspective. We've seen the T half-life in this study going out even with our lowest dose to 24, 36, and even to 48 hours. So we expect that we will have a good impact on the PBR. And from the PK profile, that's what we saw in the healthy volunteer study. There's no reason to believe that that would be significantly different in the PH patient.
spk02: Thank you. Our next question comes from Jeff Han from Morgan Stanley. Please, Jeff, your line is now open.
spk05: Hi, this is Melina for Jeff. Thanks for taking our questions. Can you talk a little bit more about, for brentocaptive, the CRS and HS indications, what are the determining factors to advance those indications into the clinic this year? Is there any specific data that you're waiting on for each indication? Yep, thank you.
spk11: Yeah, no, I appreciate that. I would say that we went through a pretty significant process, and maybe, Roger, you want to talk a little bit about that, and then, Martino, I'll ask you to comment on the logic scientifically. Yeah, sure. Thanks, Will. So we actually did a pretty exhaustive process working with some external partners. We screened diseases, and we actually ended up screening about 150 neutrophil-mediated diseases. Our next step, as we sort of narrowed that down, was to look at the disease states that were primarily driven by neutrophil involvement, and we skinnyed that list down to about a little more than 60 diseases. From there, we then looked at the epi, and we wanted to understand the size of the opportunity. We looked at the burden of the disease and narrowed that final list down. And then as we selected CRS and HS, We really focused on, number one, the science, so obviously driven by neutrophil involvement, the unmet need of the patients, and importantly, the competitive intensity, which is somewhat related to the unmet need of the patients. But in HS, there's only one approved therapy, as we mentioned, which is Sumira. And in CRS without nasal polyps, which is the neutrophilic phenotype of the disease, there are no approved therapies. And that's counter to the CRS with nasal polyps, where there's a number of biologics to fix them. Nucala, for example, that are targeting that portion of the population. So the competitive intensity is really attracted to us. And then finally, as I mentioned in our preparer comments, as we looked at pricing, we expect that the frenzocats will be supported in bronchiectasis with some attractive pricing. And we wanted to make sure that across our indications that we felt that payers would reimburse us at that same sustainable attractive pricing. And we think across our disease states with bronchiectasis, CF, CRS, and NHS, that we will be able to achieve that. So we feel very good about these disease states we're targeting now and the impact that we're going to bring to patients.
spk08: Yeah, and about scientific rationale. So there are no really good preclinical models for both of these diseases, but they are both associated with neutrophil inflammation. And if you look at CRS without nasal polyps, neutrophils play a key role in the fibrotic remodeling of the mucous membrane inside the sinuses. This remodeling leads over time to tissue damage and worsening and worsening of that disease. So from both in CRS and in HS, the neutrophil component is an important driver. And in HS, The neutrophils are prominent, and you see them in the affected skin lesion. What you also see in this affected skin lesion is that an uncontrolled release of this NSP leads to a high contribution and a presence of NETs. And there is a correlation between this NET formation and the severity of the disease. So for both of them, prensocaptive attracts what is the affected cell, and that is the neutrophilic activity through the TPP1 inhibition.
spk11: And I would just say we are moving forward with all speed in both of these indications. You saw draft designs of clinical trials in the slides today and the discussion that Martina provided. Those are going to continue to be refined. We've had very good KOL interactions, very strongly supportive of pursuing these. The only thing that holds us back from doing perhaps even more of what Roger was indicating is resource and thinking carefully about balancing how many eggs to put in this particular basket. We have excellent data in bronchiectasis. We have a very strong scientific rationale for these next three indications, as you've just heard. And I think what this really represents is the tip of the iceberg for DPP-1 inhibition in neutrophil-mediated diseases. We have really unlocked a pathway here. And I think the potential for brenzocatib to get even bigger than it already is is very real. And that puts this into a... a pretty enticing blockbuster category. So lots of work to be done and validation to be provided behind that ambition. But I think the more we look at this and the more science we study, the more excited we get.
spk05: Great. Thank you for all that detail. And if I can just ask one more quick one on the T P I P program, I think the phase two a data was pushed back originally from the first half this year to just 2022. Have you gotten any sense from prospective participants what they need to see in order to be willing to go into the ICU, particularly during these winter months when COVID rates might be higher?
spk11: Yeah, this is a frustrating one for all of us. Look, the Phase IIa study has been in design and out there for some time. The big challenge here is that, as far as we know, there is no precedent for this study. Doing a right heart catheterization on somebody that lasts more than about four hours, we're not aware of studies that have ever done that. We're proposing to do it for 24 hours. And what's interesting about that is that the key opinion leaders who have opened their centers to pursue this are enthusiastic about doing so. They really think this data is going to de-risk this program's potential very substantially. So we are excited to get the data. Finding someone to volunteer who has PA in an advanced state and is willing to have a right heart catheterization for 24 hours while they sit in an ICU surrounded by COVID-infected patients, that's a very high bar. I think we probably underestimated how severe an aspect that was. But we're pursuing it. We have identified some patients by name. They will indicate at times that they want to come in, and then they get a little bit nervous. So we're trying to work as productively as we can. And as Omicron recedes, I think we have a very good chance of getting those patients. That's why we've sort of said, look, to get all the data, it may take a little bit longer. But importantly, we plan to get the data. And once we get it, we will share it. And that could be at any time across the year.
spk05: Great. Thanks very much.
spk02: Thank you. Our next question comes from Ritu Baral from Cohen. Please, Ritu, your line is now open.
spk06: Good morning, guys. Thanks for taking the question. I wanted to ask about Aspen and what you're seeing so far. Have you been looking at a blended event rate for exacerbations in Aspen? How are they comparing to expectations, and frankly, should we be thinking about any COVID impacts on exacerbation rates in this population, you know, up, down, with waves, and whether this seems to be happening more with COVID in this population, if you could just help frame that.
spk08: Yes. So what we're doing is we're in a blinded fashion looking at the events rate on a weekly basis. And is what we're seeing matching our assumptions? So from that perspective, what we're seeing is matching our assumptions at this time. When it comes to COVID, There is an additional aspect in every respiratory study right now. So we also know which patients, how many patients have COVID. So remember, all of this is in a blinded way. We don't see the individual arms, but we have a clear view of what is the patient population. Do we see anything that deviates right now from our assumptions? And at this point in time, we see. what we had estimated.
spk11: And similar to what we saw in Willow.
spk08: And similar to what we saw in Willow.
spk11: So we're in a great spot right now, Ritu. I mean, this trial is not only enrolling quickly, but the monitoring that Martina is describing has gone remarkably well. And that is something, as she said, we're tracking on a weekly basis. So we are all over this.
spk06: Got it. And then a question for Roger, just on the new Brenzo indications. As you think about that severe CRS population, you think about HS, who are the treating physicians that you think will ultimately be commercially targeted? Are they like EMTs and then specific derms, or are they sort of more broad than how I might be thinking about it?
spk11: Yeah, thanks for two. So you're right. For the CRS, it's the ENTs. So these would be the folks that will primarily be performing the surgeries. So we will be targeting the ENTs. And to be honest, we'll need to figure out, you know, there's about 10,000 to 12,000 ENTs in the U.S., approximately the same number for derms. You know, we'll need to segment that population and do the work to figure out who we're going to be reaching. out to address these diseases and see who are the experts in that field. But yeah, it's ENTs and then with the derms, we'll do the same process, right? About 10 to 12,000. We'll take a look at probably a really good indicator is you see a dermatologist is using Humira, that's going to give you a really good lead as to who you need to be talking about to bring Brenzo to them. So we'll update you later with more specifics about that, but those are the specialists that we're focusing on.
spk02: Thank you. Our next question comes from Judah from Credit Suisse. Please, Judah, your line is now open.
spk09: Hi, guys. Thanks for taking the question. First, just a quick follow-up on Aspen. You mentioned kind of the 50% enrollment versus internal projections. Did those change at any time tied to COVID, or is that kind of, you know, an initial projection that stuck? And then you did talk about enrollment timelines, does that kind of foretell a readout in kind of the mid 2024 range?
spk11: Well, these are consistent. I mean, the internal projections were set after COVID was underway, as you might recall. So they certainly contemplated that. I would say We took a pretty aggressive line on what we were trying to accomplish here, as we described early on. We were going to really resource this trial and give it our best efforts. And I would say even in the context of those ambitions, this has outperformed. And I think what we're trying to put our finger on today is that, you know, a part of that is coming from the enthusiasm that surrounds the arrival of this potential medicine described by someone at the American Thoracic Society as potentially the holy grail of pulmonary medicine. So there's real palpable enthusiasm for this program out there, and that's affecting enrollment. I think the other question was? timing for data so this is a 13-month study 12 months on on drug and then one month off drug so you can you know run the math off of whenever um we're finally fully enrolled it'll be you know roughly 13 months plus the time to lock the database and release it in top line form so we say approximately this time next year we should be fully enrolled okay that's helpful and then there were a couple comments just around
spk09: kind of cash allocation priorities, you know, up front in the presentation and then kind of toward the end and not allocating, over-allocating to that pillar four. Can you give us a little bit more color around priorities for cash allocation? Are there specific areas you're thinking about that, you know, you may need more, whether it's, you know, accelerating on-call enrollment or, you know, maybe the allocated sales force or, you know, pushing these new Brenzo indications? Just any color would be helpful.
spk11: Well, the first thing I would say is, as we think about the four pillars, obviously the largest spend is on the first two at the moment, where we have pivotal trials that are global in reach and large in scope. TPIP probably follows behind that. And then the fourth pillar punches way above its weight with very little resource because it's an earlier stage. And importantly, the medicines that are being produced there they proved to be effective, have a potentially shorter pathway through the regulatory maze because they can be highly impactful to very severe patients. So we have a long way to go to accomplish that, but I'm excited about the prospects of that. And we'll have more to say about the fourth pillar in detail in the second half of this year when we do an R&D day. Hopefully you noticed on the slide where we've enumerated nine different programs, you get some sense for how productive this engine already is and where it could lead us as a company. It's very exciting. I don't know, Sarah, if you want to talk about guidance for any of those different spends and how we're thinking about it.
spk08: Yeah, sure. You know, as Will mentioned, our largest, you know, focus from a capital prioritization perspective is around the Eric Case and Brentso programs. And so as we think about Arise, Aspen, Encore, we are resourcing those programs and ensuring those programs are as successful as they can be. And so as you see the success that we've had with Aspen, you know, over 50% involved. Just a degree of that study, just as a reminder, that means it's over 800 patients that we've involved in about a year. That's pretty remarkable if you think about comparator trials. So, you know, we are resourcing these programs appropriately. And Martina and I stay in close contact around prioritizations around all four pillars. Translational medicine, it's an immaterial spend for the amount of answers and questions we're going to be able to get out of that pillar.
spk02: Great. Thank you. Thank you. Our next question comes from Joseph Swartz from SVB Learing. Please, Joseph, your line is now open.
spk07: Hi, I'm jury valiant for Joe. Thank you for taking our questions. First is on pricing in Japan. Does our case get renegotiated after the first year in Japan?
spk11: Yeah, thanks for the question. There will be pricing adjustments for our case in Japan. We're not anticipating it for the first year, but there are, I think it's every two years that we're anticipating that there will be pricing adjustments potentially in Japan. It's not a given, but we're anticipating that there may be those renegotiations every couple of years.
spk07: Okay, great. Thank you. And then I forget to squeeze one in. For Arise, I believe the first patient was dosed last late December, late December, and it's like about 14 months to get 50% enrollment. You know, curious, what gives you confidence that the ramp up of enrollment could happen in the next 10 months or so of the year that's remaining? You know, are you planning to add more sites or are you detecting more interest? Any comment on that would be helpful. Thank you very much.
spk11: Yeah, and as you heard in Martina's comments, one of the challenges of MTM studies is just that these patients are very skittish, particularly in the global pandemic. We've been through this before with two other studies in the refractory population, both Phase II and Phase IV. phase three, so we're accustomed to it. If you look across this disease state, this is sort of the typical approach. What's interesting is that notwithstanding getting them in the clinical setting, the commercial opportunity that gets represented by this, the uptake is quite substantial. So we're excited to get to the other side of Arise and Encore because of what we think it's going to represent. There are a lot of patients out there that are going to benefit from this. It is also important to remember that we're asking in the ARISE study for patients to take the drug for six months and then one month off, and that is not what guidelines call for. So it's a little bit of a higher hurdle to get them to step into ARISE. It's one of the reasons why we think ENCORE is going to enroll faster. There are several countries that are now participating in ARISE that are participating in ENCORE. And so that will also add additional sites and enrollment horsepower to ON4 once ARISE is completed. But, you know, we know what the screening is. We know what the front end of the funnel is, if you will. And that's where our confidence comes from, that we think we'll be able to complete this in due time.
spk02: Thank you. Our next question comes from Stephen Wiley from Stifel. Please, Stephen, your line is now open.
spk10: Yeah. Good morning. Thanks for taking the questions. Um, maybe just to follow up on the last, on the last question, I think there was a comment that Martina made around, um, screen failure rate that you guys were seeing in, I believe, it was the Reiser Encore being, I think, somewhere north of 40%. And I was just wondering if you could maybe kind of provide some commentary around what seems to be driving that specifically and whether or not that's in line with prior studies that you've done in this disease study, I guess, specifically Convirt.
spk08: Yeah. The first thing to remember is that prior studies that we've done, a convert study within a refractory population, so those are already patients that are diagnosed and they haven't responded to treatment. So you get this positive sputum culture already when patients come to physicians and they are at the site. In the frontline indications, so these are naive patients, and very often for these patients to produce sputum is already hard. then to actually get a positive sputum culture is the next hurdle. And in addition, today, What you often have to do with this patient to actually help them to induce sputum production. So there is an element of that that sites don't do this today that's related to the COVID guidances that they often have. And then it takes a significant amount of time until you really get to a culture that is positive. And we want to ensure that we have a high-quality culture and we have the right patient. You don't want patients in the study who just have colonization, but they don't really have a good positive culture. So that is part of that. Now, it's a different environment when you're in a study situation than what you would be having in the normal clinical practice setting. There is a higher hurdle on that. And that's part of it. So we've seen this higher screen failure rates often because it's very hard for them to produce it. They just can't come up with it. Then you have to wait until you get that positive culture to make sure we have the right patient in this study. Those are very big drivers for the screen failure rates as well.
spk10: Okay. That's helpful. I guess just with respect to the phase two, a study for Brents Academy CF, I think prior guidance maybe suggested that was going to be a 22 disclosure. I think you're not maybe talking really 23. Maybe it's just semantics. But is there anything rate limiting there in terms of enrollment? Is that is that COVID related? Is that you pushing dose escalation a little bit higher than you perhaps were before?
spk11: No, that doesn't really change. All we're really trying to indicate is that at this stage, it's hard to predict exactly what the enrollment path will be. There's no new information that would redirect the timing of that. We'll update you throughout the year as we see what the progress is. I think if we've added that extra little bit of space, it's in the event that we were to go up to 65 milligrams, for example. Martina talked about the three doses we're currently targeting. Depending on how patients respond, we may need to go to 65. And so to do that might take a little bit longer. That's all that's really playing out there.
spk10: All right. Thanks for your questions.
spk02: Thank you. Our next question comes from Lisa Baker from Everscore. Please, Lisa, your line is now open.
spk01: Hi, thanks for taking the question and that's on all the updates. I just wanted to understand a little bit more about the dynamics of how you're thinking about Eric Hayes. You're kind of well into the quarter already for the first quarter. Any updates on sort of trends you're seeing? And then as you think about guidance for next year, can you give any color on is the growth coming primarily ex-U.S., U.S.? Maybe you can give us some breakdown of how you're thinking about the 30% growth across the different regions?
spk08: Sure, happy to. Thanks, Lisa, for the question. So, you know, we're, you know, excited and encouraged to be able to reinstate revenue guidance. First time, you know, in two years that we've been, you know, coming out with revenue guidance with a 30% year-over-year growth is, you know, substantial growth. We anticipate that we will see growth from all three of our regions. As I mentioned earlier in the prepared remarks, Q1 is always the toughest in the U.S. due to the donut hole reset and all of those good things, as you've historically seen throughout our Q1s. And as Roger mentioned in his remarks around sort of the nuances in the japan market on the two-week restriction being lifted in the june time frame so some you know nuances as you think about the different regions but we do expect to see growth in all three of our regions and we have as a global society gotten to a place where we understand covet and folks are you know learning how to live in this new environment. So hopefully that gives you a little more color.
spk11: Maybe I'll just add in a couple of comments because I think what we're seeing, and as Sarah had said, you know, first quarter is always a tough quarter for the U.S. with the co-pays and the deductible resets and so forth. But what we're really encouraged to, if we look at Omicron and look what's happened with COVID, we got, you know, the whole country got hit with that at various times. And we're seeing, you know, it's still a regional impact, but, you know, we're seeing trends in the Northeast where hospitalizations are just plummeting in the U.S. And we're seeing some specific areas that we, where our sales reps are able to get back in front of customers and have more in-person calls. And we think that that's really important. We know the pulmonologists have been particularly hit hard in IDs with the whole COVID situation. And as we see that start to subside and knock on wood, we're all hoping we're getting to the other side of this. We think we'll see patients coming back in. We think a lot of these pulmonologists are going to be really focused on respiratory health. Everybody's focused on long COVID. Understanding the impact of that disease, I think that's going to drive index of suspicion for MTM and for other comorbidities and focusing on lung health. So, you know, we're really optimistic for growth across our regions. We've got a number of catalysts in Europe with the reimbursement decisions. In Japan, we're really thrilled with how the launch has progressed in Japan. You know, we're watching what's happening with Omicron there as well. The data I had just seen showed that actually it seems to be hitting their population harder than it's hit the U.S. and Europe. The deaths that they've actually recorded in Japan were higher than what they saw in the summer, which was the Delta variant. So it's had a really pretty profound impact. I mean, there's some theories floating around. I think the boosted population in Japan is about 9%. was the data that I heard, which is significantly less than what we've seen in Western countries. But if we see the same pattern there, where you see it peaking and then receding dramatically, I think that we'll continue that launch at pace. And we have the catalysts of the Japanese society providing that input and recommendation for ARIC-A the co-pay dynamic that will come with the two-week restriction being lifted in June, we're really optimistic it will drive that growth in Japan as well. So across our regions, we're really optimistic, and that's reflected in what we try to lay out there as our guidance.
spk01: Okay, great. And then just on the – for Japan and in Europe, does this reflect the – the kind of 2021 numbers you've provided that mostly, uh, end user demand, or is there any kind of channel fill there or anything about that? I know you kind of, at least in Japan launched fairly recently, and I'm just trying to understand if there's, is there's this channel fill dynamic or if that's really reflecting end user demand. And then for Europe, how do you get to a point where you have a better sense of, you know, what the patient numbers is just like our, sorry, just because where you're at already in terms of, you know, The share you seem to be getting, it's already pretty substantial. And I'm just wondering when you might have a better handle on actually how many patients there are available out there.
spk11: Yeah, so we don't see that. I think your first question was really, are we seeing stocking, right? So are we putting products into the channel? And we work with wholesalers in Japan, and this is reflecting user demand. So we sell the devices directly into the hospitals, and in our case, it goes to the wholesalers and to the hospitals. But because it's a fairly expensive product, you don't see a lot of stocking and carrying of that inventory. And in Europe, it's the same phenomenon, right? So we don't have that kind of phenomenon occurring. And what was the second question? Oh, the 1,400 patients. Yeah, sorry. Thanks. Yeah, look, I think... We're low to put out estimates that aren't supported by the literature, right? So I think everything we've looked at and all the literature that's available points to those 1,400 refractory patients. We're really skeptical about that. We think it is a larger number for a number of reasons. The KOLs see these patients. They are anxious for the therapy, as you mentioned. We're actually seeing some substantial revenue already from Europe without reimbursement, and we had the name patient program in place there. And so we think over time, if you think about the risk factors for NTM, it's an elderly population. If you've got a history of smoking, it's proximity to the water. All of those things are true in Europe as they are in the U.S. and Japan. So we think that the population may be understated in the literature. We don't have anything hard that we can point to around that, so we're conservative as we think about what we represent as the market might look like. But over time, we'll see that and we'll validate that. It'll take longer for us to grow that market. There is more of a medical center of excellence kind of an approach in Europe. But we think with an approved therapy that's reimbursed, you'll see these patients be treated, you'll see them identified, and we'll see that opportunity grow over time.
spk02: Thank you. As a reminder, to ask any further question, please press the star followed by one on your telephone keypads now. Our next question comes from Jennifer Kim from Kantor. Please, Jennifer, your line is now open.
spk04: Hey, everyone. Thanks for taking my questions. Maybe starting with TPIP, in terms of timing for the Phase 2B trial, clinical trials have an estimated primary completion date of February 2024. And I know that's not the most reliable indicator, but I'm wondering, based on how enrollment has moved for that asset in the Phase 2A and the enrollment we've seen with other assets as well, is it fair to call that an aggressive timeline or is it too early to say for now?
spk11: I think it's too early to say what the timeline will be for that. That's why we didn't provide it in the spoken comments. What I would draw your attention to is that I think it's very different to be enrolling for this Phase 2B trial and the Phase 2 PHILD trial than it is the 2A trial. The 2A is really blocked by the onerous nature of the protocol where a patient has to have the right heart cap for 24 hours. And so getting volunteers to go into that is challenging. Both of these Phase II trials, the Phase IIb and PAH and the Phase II and PHILD, are following a fairly standard protocol approach. And so there's good precedent out there for enrolling patients in this kind of trial. The patients are accustomed to it. It's just a question of executing it, and I think the team has proven its worth in that regard. So I'm confident that they will deliver the enrollment in as rapid a time as quality will allow.
spk04: Okay, great. And maybe one quick second question. For Ericase in Japan, you've talked about the two-week prescription limit and the COVID impact as, I guess, the two things sort of restricting growth in 2022. And I'm wondering broadly, what level of impact do each of these things have in 2022 in your mind? I'm just thinking about how we should start to think about 2023 as those factors go away. Thanks.
spk11: Yeah, thanks. So first of all, I just want to say I think the Japanese team has done an amazing job sales that we reported from last year in just a little bit more than six months, a little bit less than six months of sales. And so we expect this trajectory to continue apace. I think the impact of COVID and Omicron is real. We are having trouble accessing physicians in person because they're being pulled to their hospital duties to take care of these patients. And is restricting hospital beds. So even if they're unused, which if you look at the numbers, they're probably not a lot of unused right now, but they're restricting hospital beds and reserving them for COVID patients. And recall, we had talked about earlier, there's a predication in Japan for physicians to start our case patients in the hospital for at least a couple of days so they can monitor them. product okay. So we think that it's hopefully a first quarter phenomenon, right? So where we're seeing that Omicron will peak, we'll get on the other side of this and be able to return to some sense of normalcy. The two-week prescription, I think, is a real issue. I think what we've seen is the early adoption has been for those patients who have been waiting for, in our case, have more severe patients and are willing to look past that copay burden for them to start. I think once that's lifted, we'll see a pretty strong reaction, both from the physicians and prescribed, for their patients because, of course, they're sensitive to the economic burden of the patient as it's mostly elderly. And also for the patient, they'll be able to receive up to three months of medicine for the same copay that they currently receive up to one month right now. So I think we're really excited about and have confidence in the Japanese launch. I think we've got a couple of catalysts, and the second half I think will be a stronger uptake because of those factors.
spk02: Thank you. As a final reminder, to ask any further questions, please press the star followed by one on your telephone keypad now. The next question comes from Anita Dusla from Berenberg. Please, Anita, your line is now open.
spk00: Hi, good morning. Thank you for the update and guidance, and also congrats on the results. I have a question. Sorry if I missed this in your commentary. For the application of Brenzo-cative in CRS and HS, would you be taking both, investigating that in both of those indications this year, or is there a preference, one or the other, and if so, maybe you could talk about the rationale, why?
spk11: Yeah, so... So in response to the first question, I would say we are moving both forward. We have thought in our minds that we would bring one into the clinic by the end of this year. It's not final yet, but that is certainly our current inclination. Both are equally compelling. It's hard to choose between them to be very candid. I think our preference because of the potential in these diseases is to bring them both forward as quickly as possible. But we're trying to work a balance between resource deployment and the opportunity that they represent.
spk00: Okay, thank you. And then I know you mentioned that about that, you know, you were looking at, and from the screening, these two indications kind of were given preference. So I just wanted to know, like, potentially, would the translocated find applications in some percentage of that number that you had mentioned?
spk11: Yeah, to be clear, we think that what we've unlocked here is the DPP-1 inhibition pathway, that that interference with the inflammatory cascade is really quite profound in its potential application. So we start with these four indications, which rise to the top as the most probable for impact. But to remind you, we've already done preclinical work in other indications as well, like rheumatoid arthritis and lupus nephritis and some other very substantial indications. For a variety of reasons, it doesn't make sense for us to pursue those clinically, but we certainly are protecting them from an intellectual property standpoint And so where that preclinical work gets done and validates its potential application, we have pursued the IP around that. Would we go into diseases beyond this? If we had the resources down the road, yes, we would. I think this pathway presents a very substantial and broad opportunity. I can't emphasize that enough. And I think as we learn more and the scientific rationale is clear and the patient need is clear, those are things we will continue to evaluate and seriously consider pursuing.
spk02: Thank you. We currently have no further questions, so we'll hand over back to Will Lewis for any final remarks.
spk11: Thank you all for joining us this morning.
spk02: This concludes today's call. Thank you so much for joining. You may now disconnect your lines.
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